Polymer formulations for nasolacrimal stimulation

ABSTRACT

Described herein are polymer formulations for facilitating electrical stimulation of nasal or sinus tissue. The polymer formulations may be hydrogels that are prepared by a UV cross-linking process. The hydrogels may be included as a component of nasal stimulator devices that electrically stimulate the lacrimal gland to improve tear production and treat dry eye. Additionally, devices and methods for manufacturing the nasal stimulators, including shaping of the hydrogel, are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/944,340, filed on Feb. 25, 2014, U.S. Provisional Application No.62/027,139, filed on Jul. 21, 2014, U.S. Provisional Application No.62/035,221, filed on Aug. 8, 2014, and U.S. Provisional Application No.62/067,350, filed on Oct. 22, 2014. Each of the aforementioneddisclosures is hereby incorporated by reference in its entirety.

FIELD

Described herein are polymer formulations that provide electricalcontact between an electrode and a nasal or sinus tissue. Specifically,hydrogel formulations that are cross-linked using UV radiation aredescribed. Methods of manufacturing the hydrogels and methods oftreating dry eye with nasal stimulator devices including the hydrogelsare also described.

BACKGROUND

Dry eye disease is a major eye condition throughout the world for whichno permanent cure is currently available. For example, it has beenestimated that the current average annual cost of treating dry eyedisease amounts to $850 per person (Yu, J., Andre, C. V., and Fairchild,C. J. “The economic burden of dry eye disease in the United States: adecision tree analysis.” Cornea 30 4 (2011): 379-387). Epidemiologicalestimates of frequency of incidence of dry eye disease vary widely,depending on the symptoms being monitored. For example, Friedman reportsthat the incidence of dry eye disease ranges from 5% to 35% globally(Friedman, N. “Impact of dry eye disease and impact on quality of life.”Current Opinion in Ophthalmology 21 (2010): 310-316).

Current treatments include the use of lubricants (e.g., hydroxymethyland sodium carboxypropyl cellulose, generally known as artificialtears), anti-inflammatory therapies (e.g., corticosteroids andimmunomodulators such as cyclosporin), tear retention therapies (e.g.,punctal plugs), and treatment of underlying causes such as meibomiangland dysfunction, lid abnormalities, etc. These treatments have beenshown to have a mild to moderate improvement in the quality of life ofthe patient. For example, the Lacrisert® ophthalmic insert (Aton Phama,Lawrenceville, N.J.), a hydroxypropyl cellulose ophthalmic insert placedin the inferior eyelid cul-de-sac, was shown to have a 21% improvementin ocular surface disease index scores by McDonald, et al. (McDonald, M.B., D'Aversa, Perry H. D., et al. “Hydroxypropyl cellulose ophthalmicinserts (Lacrisert) reduce the signs and symptoms of dry eye syndrome.”Trans Am Ophthalmol Soc 107 (2009): 214-222). However, these treatmentsoften require multiple administrations per day, and typically do notprevent long term damage to the ocular surface, often caused by thechemical being administered. For example, it is known that preservatives(e.g., benzalkonium chloride) can cause damage to the ocular surface andcause irritation.

Accordingly, the development of alternative treatments for dry eyesyndrome would be useful. In particular, treatments that do not involvelong term administration of drug therapy would be beneficial. Treatmentswith simplified administration regimens would further be desirable.

SUMMARY

Described herein are polymer formulations for facilitating electricalstimulation of nasal or sinus tissue. The polymer formulations may formhydrogels that are prepared by a cross-linking process using UV orvisible light. In some applications the hydrogels may be included as acomponent of devices (referred to here and throughout as nasalstimulator devices or nasostimulator devices) that electricallystimulate the lacrimal gland via a nasal or sinus afferent nerve inpatients suffering from dry eye to improve tear production. The nasalstimulators may be used to treat dry eye of varying etiology. Forexample, they may be used to treat dry eye due to age, hormonalimbalances, side effects of medication, and medical conditions such asSjogren's syndrome, lupus, scleroderma, thyroid disorders, etc.

Generally, the polymer formulations may form electrically conductivehydrogels comprised of various monomers. The monomers may be the same ordifferent. The electrically conductive hydrogel formulations may includea first monomer; a second monomer; and a photoinitiator. The use of anacrylate monomer, a silane monomer, an acrylic terminated silanemonomer, and/or an acrylic terminated siloxane monomer as the firstmonomer or sole monomer component of the formulation may be beneficial.The electrically conductive hydrogel will typically have one or morecharacteristics that adapt it for use with a nasal stimulator device. Insome instances, the electrically conductive hydrogel is a hydrogel withhigh water content, as further described below. As used herein andthroughout, the terms “formulation,” “polymer formulation,” “hydrogelformulation,” “electrically conductive hydrogel formulation,”“hydrogel,” and “electrically conductive hydrogel” can refer toformulations comprising monomers and mixtures of monomers, before orafter they have been cured, depending on the context of how the term isused. It is understood that either the uncured or cured formulationscomprise monomers or a mixture of monomers.

Processes for producing electrically conductive hydrogels are alsodescribed herein. The processes may generally include the steps ofmixing a first monomer, a second monomer, and a photoinitiator toprepare a formulation, where the first monomer is an acrylate monomer;and irradiating the formulation with UV radiation to cross-link theformulation. The formulation may be cross-linked by covalent bonds orionic bonds to form the hydrogel.

Methods for manufacturing the nasal stimulator devices, includingshaping of the conductive hydrogel, e.g., to form a bulge that mayenhance contact of the hydrogel to nasal mucosa, and attaching the tipassembly with or without the shaped hydrogel to a base unit of the nasalstimulator devices, are also described herein. The methods for shapingthe hydrogel are further described below and may comprise dipping thetip assembly into the hydrogel, using the tip assembly to scoop hydrogeltherein, molding or casting the hydrogel, or dispensing the hydrogelinto the tip assembly through a window disposed therethrough. The tipassemblies comprising the shaped hydrogel may be stored in a dispensingcassette for later attachment to a base unit of the nasal stimulatordevice, as further described below.

In addition, described herein are methods for stimulating the nasalcavity or the lacrimal gland comprising placing an arm of a nasalstimulator device against a nasal or a sinus tissue, the arm having adistal end and an electrically conductive hydrogel disposed at thedistal end; and activating the nasal stimulator device to provideelectrical stimulation to the nasal or the sinus tissue. Theelectrically conductive hydrogel is typically used to facilitate anelectrical connection between the nasal stimulator device and the nasalor the sinus tissue. These methods may be used to treat dry eye.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an exemplary nasal stimulator device having an adjustablepair of stimulator electrodes.

FIG. 2 depicts a top view of the disposable component of anotherexemplary nasal stimulator device including a pair of spring-likeelectrodes substantially enclosed by an opaque sleeve.

FIGS. 3A-3C depict exemplary configurations of the electricallyconductive polymer provided in the disposable component of a nasalstimulator device. FIG. 3A shows a perspective view of the stimulatorelectrode surrounded by an opaque polymeric sleeve. FIG. 3B is across-sectional view of the stimulator electrode in FIG. 3A showing anelectrically conductive polymer disposed within the tip portion. FIG. 3Bdepicts a stylized view of the stimulator electrode in FIG. 3A where theconductive polymer forms a shell around the distal end of the polymericsleeve.

FIG. 4 depicts an exemplary disposable mold for use in forming thehydrogel component of a nasal stimulator device.

FIG. 5 illustrates an exemplary assembly process for the disposablecomponent.

FIG. 6 depicts the chemical structure of exemplary acrylic terminatedsilane and siloxane monomers.

FIG. 7 depicts the proposed morphology of the SB5 hydrogel formulationcured to form the electrical contact at the tip of a nasal stimulatordevice.

FIGS. 8A-8C depict exemplary methods for shaping the hydrogel includedin the nasal stimulator device tip. FIG. 8A depicts a dipping method forhydrogel shaping. FIG. 8B illustrates a scooping method for hydrogelshaping. FIG. 8C shows a hydrogel tip in which part of the tip has beenmasked during spraying of an insulator to provide a conductive portion.

FIGS. 9A-9I depict exemplary methods for shaping the hydrogel by moldingand then cutting.

FIGS. 10A-10C depict exemplary dispensing methods and dispensing devicesfor shaping the hydrogel.

FIGS. 11A-11C depict exemplary structures and methods that may be usedto help control dispensing of the hydrogel.

FIGS. 12A-12D depict an exemplary mold and casting method for shapingthe hydrogel.

FIG. 13 shows an exemplary thin walled tip capable holding largervolumes of hydrogel.

FIGS. 14A-14D show an exemplary tip assembly structure and method ofattaching the structure to a prong of a nasal stimulator device.

FIGS. 15A-15C show an exemplary method where a hydrogel preform isincluded in the tip assembly and then hydrated.

FIGS. 16A-16D depict exemplary tip assembly structures and methods ofuse that include a hinge.

FIGS. 17A-17E depict an exemplary dispensing cassette and method formanufacturing the tip assemblies.

FIGS. 18A-18D illustrate an exemplary method of attaching tip assembliesto a base unit using the dispensing cassette of FIGS. 17A-17E.

FIGS. 19A-19C show an exemplary tool and method for removing tipassemblies from the base unit.

FIGS. 20A-20B show additional exemplary tip assembly structures andassembly methods thereof.

FIGS. 21A-21B show DMA and NVP monomer extraction rates for the SB1hydrogel.

FIGS. 22A-22B show NVP monomer and methanol extraction rates for the SB2hydrogel.

FIGS. 23A-23B provide data relating to hydration of the SB1 and SB2hydrogels as a function of electrical resistance.

FIGS. 24A-24B provide data relating to the hydration of the SB2 and SB3hydrogels as a function of electrical resistance.

FIG. 25 provides data relating to the hydration of the SB4A and SB4Bhydrogels as a function of electrical resistance.

FIGS. 26A-26B provide data relating to expansion of the SB2 and SB3hydrogels due to hydration.

FIGS. 27A-27B provide data relating to expansion of the SB4A and SB4Bhydrogels due to hydration.

FIGS. 28A-28C show DMA and NVP monomer, and methanol extraction ratesfor the SB5 hydrogel.

FIG. 29 provides data relating to the hydration of the SB5 hydrogel as afunction of electrical resistance.

FIGS. 30A-30C provide data relating to expansion of the SB5 hydrogel dueto hydration.

DETAILED DESCRIPTION

The polymer formulations described herein are generally hydrogels thatmay be used to facilitate an electrical connection between an electrodeof a nasal stimulator device and nasal or sinus tissue, as mentionedabove. Accordingly, the hydrogels are biocompatible and formed to benon-irritating and non-abrasive to nasal and sinus tissue. The hydrogelsare generally also formed so that they do not break or shatter duringinsertion or use, and have moderate adhesion to nasal or sinus tissue inorder to minimize contact resistance, heating, and heat damage to thetissue it contacts. The hydrogels may be prepared by cross-linking ofvarious monomers using UV or visible light. The nasal stimulator devicemay include a disposable component and a reusable component. Thedisposable component may generally include a pair of stimulatorelectrodes and the electrically conductive hydrogel, and the reusablecomponent a source of electrical energy for the stimulator electrodes.However, in some instances the nasal stimulator device can be made to becompletely disposable.

Electrically Conductive Hydrogel Formulations

The electrically conductive hydrogels (“conductive hydrogels”) maycomprise any monomer that is capable of providing a formulation suitablefor use with nasal or sinus tissue, and suitable to facilitate anelectrical connection between a nasal stimulator device, e.g., ahand-held nasal stimulator device, and nasal or sinus tissue. Theformulation is typically prepared by UV cross-linking of the monomers,as further described below. In some variations, the formulations provideelectrically conductive acrylate/methacrylate/vinyl hydrogels. In othervariations, the formulations provide electrically conductivesilicone-acrylate hydrogels.

In one variation, the conductive hydrogel formulation may include afirst monomer; a second monomer; and a photoinitiator, where the firstmonomer is an acrylate monomer. Here the acrylate monomer may be amonofunctional monomer, a difunctional monomer, a trifunctional monomer,or a precursor or a derivative thereof.

Examples of monofunctional monomers that may be included in theformulations include without limitation, acrylic acid, butyl acrylate,butyl methacrylate, 2-chloroethyl vinyl ether, ethyl acrylate,2-ethylhexyl acrylate, furfuryl acrylate, glycerol monomethacrylate,hydroxyethyl methacrylate, methacrylic acid, methoxy polyethylene glycoldimethacrylate, methoxy polyethylene glycol monoacrylate, and aminoethylmethacrylate.

The difunctional monomers that may be used in the formulations include,but are not limited to, diethylene glycol diacrylate, ethylene glycoldimethacrylate, neopenyl glycol diacrylate, polyethylene glycoldiacrylate, polyethylene glycol di-methacrylate, triethylene glycoldiacrylate, and N,N′ dimethylene bisacrylamide.

With respect to the trifunctional monomer, examples include withoutlimitation, pentaerythritol triacrylate, propxylated glycol triacrylate,trimethylpropane triacrylate, and trimethylol propane trimethacrylate.

The first monomer and the second monomer may or may not be the same typeof monomer. Examples of second monomers include, but are not limited to,dimethylacrylamide, glycidyl methacrylate, N-vinylpyrrolidone, and1,4-butanediol diacrylate.

Silane or siloxane monomers may also be used to form an electricallyconductive hydrogel. Suitable siloxane monomers typically comprise a

group. In one variation, silane methacrylate monomers are included inthe conductive hydrogel formulations as the first and/or second monomer.For example, methacryloxypropyltris (trimethylsiloxy) silane,methacryloxymethyltris (trimethylsiloxy) silane, methacrylodxypropylbis(trimethylsioloxy) silanol, 3-methoxypropylbis(trimethylsiloxy) methylsilane, methacryloxypentamethyldisiloxane, methacryloxypropyltrimethoxysilane, and methacryloxypropyltris (methoxyethoxy) silane monomers maybe used. In further variations, acrylic terminated silane and siloxanemonomers, e.g., as shown in FIG. 6 may be used. These acrylic terminatedsilane and siloxane monomers include, but are not limited to, trimethylsilyl methacrylate, 2 (trimethylsilyloxy) ethyl methacrylate,3-(trimethyoxysilyl)propyl methacrylate, and (3-methacryloyloxypropyl)tris (trimethylsiloxy)silane. In some instances, it may be beneficial toinclude 3-methacryloxyproplyl tris (trimethyl siloxy) silane in thehydrogels. Vinyl substituted silane monomers may also be used in thehydrogel formulations. Here the silane monomer may be one that comprisesa —SiR group, where R may be hydrogen, or a methyl or an alkyl group.

Hydrogels containing siloxane monomers may retain the water they absorbover a longer exposure to air, and thus, retain their electricalconductivity for a longer period of time. The mole fraction of siloxanegroups in the silicone hydrogels may range from about 5% to about 20%.When a silane group is employed, the mole fraction of silane groups inthe hydrogels may range from about 5% to about 20%.

The conductive hydrogels may be formed by a UV cross-linking process. Inthis instance, a photoinitiator is generally included in theformulation. Photoinitiators may be any chemical compound thatdecomposes into free radicals when exposed to light, e.g., UV radiationhaving a wavelength in the range of about 350 nm to about 450 nm. Thefree radicals initiate polymerization to form cross-linked hydrogels. Inone variation, the photoinitiator initiates ring opening polymerization.In another variation, the photoinitiator initiates cationicpolymerization. In a further variation, the photoinitiator initiatespolymerization by a thiol-ene reaction.

Any suitable photoinitiator may be employed in the formulationsdescribed herein. For example, the photoinitiator may be selected fromthe group consisting of acylphosphine oxides (APOs), bisacylphosphineoxides (BAPOs), 2,2-dimethoxy-1,2-diphenylethan-1-one (Igracure®photoinitiator), benzoin ethers, benzyl ketals,alpha-dialkoxyacetophenones, alpha-hydroxyalkylphenones, alpha-aminoalkylphenones, benzophenones, thioxanthones, and combinations andderivatives thereof. In some instances, it may be useful to include anacylphosphine oxide or bisacylphospine oxide photoinitiator in theformulation.

The acylphosphine oxide photoinitiators that may be used include withoutlimitation, 2,4,6-trimethylbenzoyl-diphenylphospine oxide (TMDPO);benzoyl-diphenylphosphine oxide (BDPO);2,4,6-trimethylbenzoyl-methoxy-phenylphosphine oxide (TMMPO);phthaloyl-bis(diphenylphosphine oxide (PBDPO)),tetrafluoroterephthanoyl-bis(diphenylphosphine oxide) (TFBDPO);2,6-difluoro benzoyl-diphenylphospine oxide (DFDPO);(1-naphthoyl)diphenylphosphine oxide (NDPO); and combinations thereof.In one variation, 2,4,6-trimethylbenzoyl-diphenylphospine oxide (TMDPO)is a useful photoinitiator.

The bisacylphosphine oxide photoinitiators that may be used includewithout limitation, bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide(BTMPO); bis(2,6-dimethoxybenzoyl)-2,4,4-trimethyl-pentylphosphineoxide; 1-hydroxy-cyclohexyl-phenyl-ketone; and combinations thereof.

The conductive hydrogels described herein may further include a suitablediluent. Suitable diluents may be glycerin, isopropanol, polyethyleneglycol, water, methanol, and combinations thereof. Table 1 shows anexemplary list of monomers, photoinitiators (e.g., UV initiators), anddiluents that may be used to make the conductive hydrogels.

TABLE 1 Exemplary list of formulation monomers, diluents, and UVinitiators. Silane and Monofunctional Difunctional TrifunctionalSiloxane UV Monomers Monomers Monomers Monomers Initiators DiluentsAcrylic acid Ethylene glycol Pentaerythritol Trimethyl silyl Irgacure189 Water dimethacrylate triacrylate methacrylate (Ciba/BASF)Methacrylic acid Polyethylene Trimethyl- 2(trimethylsilyloxy) Irgacure819 Isopropanol glycol diacrylate propane Ethyl methacrylate (Ciba/BASF)(200-1500) triacrylate Methoxy Neopentyl Propoxylated 3(trimethoxysilyl)Irgacure 1173 Polyethylene polyethylene glycol diacrylate glycol propylmethacrylate (Ciba/BASF) glycol glycol monoacrylate triacrylate(300-550) Methoxy Diethylene Trimethylol 3(methacryloyloxy Lucirin TPOGlycerin polyethylene glycol diacrylate Propane propyl) tris (BASF)glycol dimethacylate trimethacrylate (trimethylsiloxy silane)Hydroxyethyl Triethylene Methanol methacrylate glycol diacrylateFurfuryl Acrylate N,N′ dimethylene bisacrylamide Glyceryl Polyethylenemonomethacrylate glycol di-methacrylate

In some variations, the monofunctional monomers are selected from Table1 and comprise no more than 80% and no less than 30% moles/mole of theformulation prior to addition of diluents. In other variations, thedifunctional monomers are selected from Table 1 and comprise no morethan 25% and no less than 5% moles/mole of the formulation prior to theaddition of diluents. In further variations, the trifunctional monomersare selected from Table 1 and comprise about 0.0 to about 5.0 moles/100moles of the formulation prior to the addition of diluents.

The conductive hydrogels will generally be formed to have one or morecharacteristics that adapt it for use with a nasal stimulator device.For example, characteristics such as electrical resistivity, maximumhydration level, tensile strength (elongation break), Young's modulus,glass transition temperature, and cross-link density, may be adjusted toadapt the conductive hydrogel for use with a nasal stimulator device.

The electrical resistivity of the conductive hydrogel may range fromabout 50 to about 2,000 Ohm·cm, or from about 150 to about 800 Ohm·cm.In one variation, the electrical resistivity ranges from about 400 toabout 800 Ohm·cm. In another variation, the electrical resistivityranges from about 200 to about 600 Ohm·cm. In a further variation, theelectrical resistivity ranges from about 150 to about 500 Ohm·cm.Alternatively, the electrical resistivity may range from about 550 toabout 600 Ohm·cm.

With respect to other characteristics of the conductive hydrogel, themaximum hydration level may range from about 35% to about 80% by weight,and the tensile strength (elongation at break) may range from about 35%and 150%, or from about 35% to about 100%, at 30% relative humidity.Here hydration level is defined as(W_(hydrated polymer)−W_(dry polymer))/W_(hydrated polymer). Young'smodulus ranges of the conductive hydrogel may range from about 0.1 toabout 1.5 MPa, or from about 0.1 to about 1.0 MPa. The glass transitiontemperature of the conductive hydrogel may range from about 5 to about65 degrees Celsius in the dry state. Furthermore, the cross-link densitymay range from about 0.01 to about 0.10 moles/mole.

The conductive hydrogel formulations may contain fillers to improve oneor more of the following: mechanical properties, cosmetic appearance,electrical properties, and cost. Suitable fillers may include withoutlimitation, silica, alumina, titanium dioxide, polyethylenemicrospheres, carbon black, nanofibers, nanoparticles, and combinationsthereof.

The conductive hydrogel formulations may be a homogenous material orthey may comprise a multiphase blend or a block copolymer withrelatively hydrophobic and relatively hydrophilic domains that haveundergone a microphase separation.

Additionally, the conductive hydrogel formulations may contain additivesthat are either soluble or present in a dispersed form in the polymermaterial. These additives may include hydrophilic molecules, cagemolecular structures, surface modifying agents, or amphiphilicmolecules. Exemplary amphiphilic molecules include without limitation,cellulose, dextran, hydroxypropyl cellulose, hydroxymethyl cellulose,hyaluronic acid, sodium hyaluronate, chitin, chitosan, crown etherderivatives, and combinations thereof.

Conductive hydrogel formulations having the following characteristicsmay be useful in facilitating electrical communication between a nasalstimulator device and nasal or sinus tissue:

-   -   Electrical resistivity ranging from 200-800 Ohm·cm, elongation        at break greater than 50% in tensile mode, and hydration level        in the range of 25-80% (hydration level being expressed as the        equilibrium swelling ratio, W_(h)/W_(G)×100, where W_(h) is the        mass of water at equilibrium at a particular temperature, and        W_(G) is the weight of the hydrated gel measured under the same        conditions);    -   Electrical resistivity at the fully hydrated state ranging from        300 to 500 Ohm·cm;    -   Equilibrium swelling ratio ranging from 35-65%;    -   Hydration level that does not change by more than approximately        10% (or 5.0 to 30 g if comparing hydrogel weight before and        after hydration), over 15 hours of continuous exposure to indoor        air at 25 degrees Celsius, with a relative humidity not less        than 30%;    -   Young's modulus ranging from 0.10 to 10 MPa in the fully        hydrated state, and a glass transition temperature of the dry        gel ranging from 5 to 65 degrees Celsius; or    -   Cross-link density ranging from 0.01 to 0.10 moles/mole.

Some variations of the conductive materials may comprise polyethylene orpolypropylene polymers filled with carbon black or metal particles.Other variations may include conducting polymers such as poly-phenylenesulfide, poly-aniline, or poly-pyrrole. Ionically conducting variationssuch as hydrophilic, cross-linked polymer networks are alsocontemplated. However, in some instances the conductive hydrogel may beneutral and comprise hydrophobic segments or domains in a hydrophilicnetwork. In yet further variations, the conductive hydrogel may compriseionic pendant groups, some of which provide ionic or electrostaticcross-linking. A conductive hydrogel that is a biocompatible,hydrophilic, cross-linked network comprising hydrophobic segments, andwhich has a glass transition temperature in the range 5 to 65 degreesCelsius, and an elongation at break in the range of 50% to 150% may beuseful.

In yet further variations, it may be beneficial for the conductivehydrogels to have a high water content, e.g., a water content of 60% orgreater, as calculated by the following formula: percentwater=(W_(hydrated hydrated gel)−W_(dry gel))/(W_(hydrated gel))×100,where W is weight. In some variations, the water content may range fromabout 60% to about 99%, from about 60% to about 95%, from about 60% toabout 90%, from about 60% to about 85%, from about 60% to about 80%,from about 60% to about 75%, from about 60% to about 70%, or from about60% to about 70%. In general, the lower limit is the amount of waterneeded to be absorbed so that the hydrogel maintains a high watercontent after several hours of exposure to air at room temperature andmoderate levels of relative humidity. The value for the upper limit ofwater content may be influenced by the need to have mechanicalrobustness, including a tensile modulus higher than about 0.1 MPa and anelongation break greater than 50%.

Exemplary conductive hydrogels having high water content may comprisecross-linked networks that include monomers such as acrylamide,methacrylamide, dimethylacrylamide, or combinations thereof. In onevariation, the high water content hydrogel includespoly-dimethylacrylamide cross-linked by potassium persulfate.

In another variation, the high water content hydrogel may comprise anionic co-monomer including, but not limited to, sodium acrylate, zincarylate, calcium acrylate, or combinations thereof. The ionic co-monomermay be used at a concentration ranging from zero to about 20 molepercent. Hydrogels using an ionic co-monomer may have a percent watercontent of 99% or more.

Hydrogels having a high water content generally have an elastic modulusranging from about 0.001 to 0.01 MPa. When employed with the nasalstimulator devices referred to herein, the hydrogels may require ahigher level of cross-linking so that the minimum elastic modulus isabout 0.1 MPa. The additional cross-linking may be provided by addingN,N′diethyl bis-acrylamide co-monomer to the hydrogel formulation. TheN,N′diethyl bis-acrylamide co-monomer may be added in an amount rangingfrom about 0.5% to about 2.0%, or from about 0.5% to about 1.0% byweight of the formulation. Exemplary conductive hydrogel formulationswith high water conduct are provided below in Table 2.

TABLE 2 Exemplary Conductive Hydrogel Formulations with High WaterContent MONOMER CONCENTRATION Function N,N′ Dimethyl acrylamide 50-90%Monomer and cross-linker N,N′ Dimethyl bisacrylamide 0.5-2.0%Cross-linker Sodium Acrylate  0-10% Monomer Zinc acrylate  0-10% MonomerPolyethylene glycol diacrylate  0-10% Cross-linker Cumyl hydroperoxide0-1% Initiator Potassium persulfate 0-1% Initiator

In some variations, it may be useful to include hydrophilic groups intothe conductive hydrogels so that the hydrogels form a relatively strongcomplex with water molecules, thereby increasing the activation energyof the dehydration process in the molecular structure of the hydrogelnetwork and reducing the drying out (or dry out) rate of the hydrogels.For example, polysaccharides may be included in the hydrogels as ahydrophilic additive since they are biocompatible, strongly bind water,and can be chemically immobilized on the hydrogel network. Thepolysaccharides that may be used include, but are not limited to,dextran sulfate, hyaluronic acid, sodium hyaluronate, hydroxymethylcellulose, chitosan, sodium alginate, and combinations thereof. When apolysaccharide additive is employed, it may be included in the hydrogelsin an amount ranging from about 0.5% to about 20%, from about 0.5% toabout 15%, from about 0.5% to about 10%, or from about 0.5% to about 5%,by weight of the formulation. The polysaccharide additive may be addedto the monomer formulation or it may be incorporated into the networkduring hydration.

The drying out rate of the hydrogel can also be substantially reduced byincluding a hydrating agent or a hydrating medium in the hydrogelformulation. For example, propylene glycol and polymers thereof can beincluded as a hydrating agent. Additionally, mixtures of propyleneglycol and water can be used as a hydrating medium. The inclusion of apropylene glycol and water mixture in the hydrogel formulation mayresult in less water being present at the hydrogel surface, and thusevaporated from, the hydrogel surface.

Propylene glycol and water can be combined in various amounts or ratiosin the hydrating medium. In some variations, the hydrating mixtures cancomprise propylene glycol in an amount between about 5 to about 85percent by volume, between about 5 to about 80 percent by volume,between about 5 to about 75 percent by volume, between about 5 to about70 percent by volume, between about 5 to about 65 percent by volume,between about 5 to about 60 percent by volume, between about 5 to about55 percent by volume, between about 5 to about 50 percent by volume,between about 5 to about 45 percent by volume, between about 5 to about40 percent by volume, between about 5 to about 35 percent by volume,between about 5 to about 30 percent by volume, between about 5 to about25 percent by volume, between about 5 to about 20 percent by volume,between about 5 to about 15 percent by volume, or between about 5 toabout 10 percent by volume. In other variations, the hydrating mixturescan comprise propylene glycol in an amount between about 20 to about 50percent by volume or between about 20 to about 35 percent by volume. Infurther variations, the hydrating mixtures can comprise propylene glycolin an amount of about 5 percent by volume, about 10 percent by volume,about 15 percent by volume, about 20 percent by volume, about 25 percentby volume, about 30 percent by volume, about 35 percent by volume, about40 percent by volume, about 45 percent by volume, about 50 percent byvolume, about 55 percent by volume, about 60 percent by volume, about 65percent by volume, about 70 percent by volume, about 75 percent byvolume, about 80 percent by volume, or about 85 percent by volume.

Water may make up the remainder of the hydrating mixtures, or in someinstances, other components may be included. The hydrating mixtures cancomprise water in an amount between about 15 to about 95 percent byvolume. For example, the hydrating mixtures can comprise water in anamount of about 15 percent by volume, about 20 percent by volume, about25 percent by volume, about 30 percent by volume, about 35 percent byvolume, about 40 percent by volume, about 45 percent by volume, about 50percent by volume, about 55 percent by volume, about 60 percent byvolume, about 65 percent by volume, about 70 percent by volume, about 75percent by volume, about 80 percent by volume, about 85 percent byvolume, about 90 percent by volume, or about 95 percent by volume.Instead of water, saline may also be used, and included in the sameamounts described as for water.

Exemplary hydrating mixtures may include propylene glycol and water (orsaline) in the following amounts: about 5 percent by volume propyleneglycol and about 95 percent by volume water; about 10 percent by volumepropylene glycol and about 90 percent by volume water; about 15 percentby volume propylene glycol and about 85 percent by volume water; about20 percent by volume propylene glycol and about 80 percent by volumewater; about 25 percent by volume propylene glycol and about 75 percentby volume water; about 30 percent by volume propylene glycol and about70 percent by volume water; about 35 percent by volume propylene glycoland about 65 percent by volume water; about 40 percent by volumepropylene glycol and about 60 percent by volume water; about 45 percentby volume propylene glycol and about 55 percent by volume water; about50 percent by volume propylene glycol and about 50 percent by volumewater; about 55 percent by volume propylene glycol and about 45 percentby volume water; about 60 percent by volume propylene glycol and about40 percent by volume water; about 65 percent by volume propylene glycoland about 35 percent by volume water; about 70 percent by volumepropylene glycol and about 30 percent by volume water; about 75 percentby volume propylene glycol and about 25 percent by volume water; about80 percent by volume propylene glycol and about 20 percent by volumewater; or about 85 percent by volume propylene glycol and about 15percent by volume water. The exemplary hydrating mediums provided belowin Table 3 may be useful in hydrogels that are employed as electricalcontacts in nasal stimulator devices.

TABLE 3 Exemplary Hydrating Mediums Amount Hydrating Hydrating HydratingHydrating Component Medium 1 Medium 2 Medium 3 Medium 4 Propylene Glycol35 40 45 50 (vol %) Water (vol %) 65 60 55 50

The hydrogels described herein generally have a functional time periodand a dry out time period. The functional time period is typically theperiod of time during which the hydrogels can be used withoutsubstantial loss of function (e.g., the impedance of the hydrogel doesnot rise higher than about 2500 Ohms). The dry out time period istypically the maximum time period of use of the hydrogel, where at theend of the period, function, e.g., stimulative function, of the hydrogelhas substantially decreased. It would be beneficial to maximize both thefunctional time period and dry out time period for the hydrogel tips ofthe nasal stimulator devices described herein to extend, e.g., theirshelf life. Table 4 provides the functional time periods, dry out timeperiods, and impedances for four exemplary hydrogel tips. All fourhydrogels included the SB5 formulation described in Example 15, butfurther included a propylene glycol hydrating medium having propyleneglycol amounts varying from about 35 percent by volume to about 50percent by volume.

TABLE 4 Exemplary Functional Time Periods, Dry Out Time Periods, andImpedances Hydrogels with Propylene Glycol (PG) Hydrating Medium 35 vol40 vol 45 vol 50 vol % PG % PG % PG % PG Functional Time 14 17.1 22 24.4Period (hours) Dry Out Time 17.8 22.1 27.1 31.0 Period (hours) Impedance(ohms) 1150 1300 1670 1600

By varying the amount or ratio of propylene glycol in the hydratingmedium, Table 4 shows that lifetime of the hydrogel tip can be tailoredto the desired indication. For example, if a nasal stimulator device isintended for single day use, it may be useful to include a 35 percent byvolume (vol %) propylene glycol hydrating medium to form the hydrogeltip. The hydrogels, whether they include a hydrating agent or hydratingmedium, or whether they do not include a hydrating agent or hydratingmedium, can be suitably sized, shaped, molded, etc. to form anelectrical contact of a nasal stimulator device. For example, thehydrogels can be included as part of a prong of a nasal stimulatordevice, generally at the tip of the prong. Although the use of thehydrating mediums in hydrogel tips for nasal or sinus stimulation hasbeen described, it should be understood that they can be used inhydrogels for other applications.

As stated above, the conductive hydrogels can be included in the prongsor tips of nasal stimulator devices and used to facilitate an electricalconnection between a nasal stimulator device and nasal or sinus tissue.Some examples of such nasal stimulator device prongs or tips areprovided in U.S. application Ser. No. 14/256,915 (U.S. Publication No.2014/0316485), entitled, “NASAL STIMULATION DEVICES AND METHODS,” filedApr. 18, 2014, the contents of which are hereby incorporated byreference in their entirety (the conductive hydrogels in U.S.application Ser. No. 14/256,915 are referred to as hydrogel electrodes).The nasal stimulator device may be configured to include a disposablecomponent that is removably attached to a reusable component or housing.An exemplary disposable component is shown in FIG. 1. In that figure,the disposable unit (100) consists of a pair of arms or prongs (102,106) that house electrodes (not shown), which are adjustable in alateral direction, and which can also be rotated or swung so as to varythe angle between them. Each electrode is provided in the form of ametal rod that is encased in a polymeric sleeve (104). Each sleeve (104)ends in a slot (108, 110), to be filled with an electrically conductingpolymer (e.g., hydrogel) that forms an electrical contact between theelectrode and nasal or sinus tissue.

Alternatively, and as illustrated in FIG. 2, the disposable unit (200)has a pair of arms or prongs (202, 204) that comprise an opaquepolymeric sleeve (206) encasing electrodes (not shown). The opaquepolymeric sleeve may be configured to completely cover the electrodes orto partially cover the electrodes. In this variation, the sleeve (206)and the electrodes are made flexible and spring like. Their flexibilityis designed to accommodate variations in the width of the nose, and theangular orientation preferred by an individual user. Similar to FIG. 1,an electrically conductive hydrogel can be disposed at the tip of theprongs (202, 204) to function as an electrical contact between theelectrode and the nasal or sinus tissue.

FIGS. 3A-3C provide exemplary configurations of the conductive hydrogelwhen employed with a nasal stimulation device. FIG. 3 shows thepolymeric sleeve (300) as an opaque tube, which surrounds the supportingelectrode inside. In this variation, the sleeve (300) ends in a slotthat is filled with a conductive polymer that provides an electricalconnection between the electrode and nasal or sinus tissue. As depictedin the cross-sectional view of FIG. 3B, the polymer (302) fills the slot(304) and forms a slightly protruding cylindrical surface for optimumcontact with nasal tissue. It may be beneficial for this polymer to besqueezable, so that it can conform to the contours of the nasal cavity,which is lined with a mucous membrane of squamous epithelium, whichtissue then transitions to become columnar respiratory epithelium. Thecavity provides drainage for the sinuses and the nasolacrimal duct, andtherefore presents a highly humid and moist environment. (Anatomy of thehuman nose, Wikipedia). In the variation shown in FIG. 3B, theconductive polymer forms a shell (306) around the end of the sleeve(300), filling the slot and extending down the sleeve to contact theelectrode.

Process for Making the Electrically Conductive Hydrogels

The process for producing the electrically conductive hydrogelsdescribed herein generally comprise the steps of: mixing a firstmonomer, a second monomer, and a photoinitiator to prepare aformulation, wherein the first monomer is an acrylate monomer; andirradiating the formulation with UV radiation to cross-link theformulation. The monomers may be ones provided above, e.g., as listed inTable 1. In some variations, the conductive hydrogel is cross-linked bycovalent bonds. In other variations, the hydrogel is cross-linked byionic bonds. In hydrogels with hydrophilic and hydrophobic domains, thehydrophobic domains may form a shell around a hydrophilic core, forminga core-shell structure. A hydrogel with a high water content (e.g.,50-70%) with a hydrophobic shell may dry out more slowly than a hydrogelwithout a hydrophobic shell, and therefore may retain its electricalconductivity for a longer period when left exposed to air in betweenuses.

In some variations, the hydrogel may be surface modified to develop arelatively more hydrophilic surface in order to further reduce skinresistance upon contact with nasal tissue. Surface modification may bedesired for hydrogels that have developed a hydrophobic shell, leadingits surface to become hydrophobic. In this application, a surface isgenerally deemed to be hydrophobic if its water contact angle (sessiledrop) exceeds 80 degrees, while it is generally deemed to be hydrophilicif the contact angle is less than 30 degrees. Surface modification maybe achieved in several ways. One method is to treat the formed hydrogelwith a low pressure plasma, produced by an RF discharge or a microwavedischarge. Suitable plasma materials include air, oxygen, and watervapor. This method is believed to cause chemical modification of themolecules on the surface, forming hydroxyl groups that render thesurface hydrophobic. Another method is to deposit a hydrophilic polymervia plasma polymerization, including plasma assisted chemical vapordeposition (PACVD), or plasma initiated chemical vapor deposition(PICVD). Suitable materials to be deposited using the plasmapolymerization method include HEMA or GMA. Yet another surfacemodification method, applicable to hydrogels with siloxane groups on thesurface (e.g., hydrogel SB5 described in Examples 15-19 below), includeschemical activation of the surface, for example, by treating the surfacewith aqueous sodium hydroxide (1-10% w/w), washing it to removeunreacted alkali, then reacting it with a hydroxyl or amino terminatedmolecule such as polyethylene glycol. In yet another method, surfacemodification may consist of the addition of a surfactant into thehydrogel formulation that migrates to the surface upon polymerization. Asurfactant is an amphiphilic molecule that exposes a hydrophilic end atthe surface of the hydrogel. Exemplary surfactants include sodiumdodecyl sulfate, salts of polyuronic acid, Triton X-80, etc.Alternatively, the hydrogel surface may be modified, e.g., to becomemore hydrophilic, by including a hydrating medium into the formulation.Exemplary hydrating mediums are described above.

The conductive hydrogel formulations may be prepared to cure to a zeroor a low expansion solid that is formulated with diluents in the sameweight fraction as the equilibrium swelling ratio of the hydrogel whenfully cured. The weight ratio of diluents to the monomer andphotoinitiator mix may be from about 35% to about 70%. Exemplarydiluents that may be employed are listed in Table 1. These diluents arewater soluble, biocompatible, and have a viscosity less than 100 CST at25 degrees Celsius.

The curing process may be caused by any suitable wavelength of light. Insome variations, the curing process is caused by irradiation with UVlight in the wavelength range of about 350 nm to about 450 nm, and iscatalyzed by one or more photoinitiators selected from Table 1. Otherphotoinitiators, also as described above may be used. For example,acylphosphine oxides and bisacylphosphine oxides that are biocompatible,and which absorb long wavelength ultraviolet radiation may be used.

Table 5 provides an exemplary list of conductive hydrogel formulationsthat were cured by irradiation with UV light at a wavelength range of300 nm to 480 nm, e.g., 350 nm to 450 nm, at a temperature ranging from10 to 65 degrees Celsius, preferably 25 to 45 degrees Celsius, and overa time period of 10 seconds to 30 minutes, e.g., 1 minute to 15 minutes,and using 2,4,6-trimethylbenzoyl-diphenylphospine oxide (TMDPO) as thephotoinitiator.

TABLE 5 Exemplary conductive hydrogel formulations. Formulation* WaterContent (%)** 1 HEMA/DMA 700CL 34 2 GMA/DMA 700CL NM 3 100% MAA/DMA700CL 44 4 HEMA/GMA/DMA 700 CL 42 5 HEMA/HEMA10/DMA 700 CL 44 6HEMA/DMAC/DMA(700) Crosslinker 50 7 HEMA/GMA/BDDA CL 41 8HEMA10/HEMA/BDDA CL 39 9 HEMA/DMAC/DMA(700) Crosslinker 57 10NVP/DMAC/HEMA 50 11 NVP/DMAC/HEMA 69 12 NVP/DMAC/HEMA 78 13NVP/DMAC/HEMA 77 14 NVP/DMAC/HEMA with glycerol diluent 77 15NVP/DMAC/HEMA 70 16 NVP/DMAC/HEMA with glycerol diluent 78 17HEMA/MEMA/PEG diluent 34 18 HEMA/MAA/DMA 700/water/PEG400 NM 19HEMA/MAA/DMA 700/water/PEG400 20 *HEMA = hydroxyethyl methacrylate; DMA= dimethylacrylamide; GMA = glycerol monomethacrylate; MAA = methacrylicacid; DMAC = dimethylacetamide; BDDA = 1,4-butanediol diacrylate; NVP =N-vinylpyrrolidone; MEMA = methoxyethyl methacrylate; HEMA10 = polyethoxy (10) ethyl methacrylate. **NM = not measured.

Other exemplary conductive hydrogel formulations are provided inExamples 1-7, and 15. Based on the data from experiments run with thesehydrogel formulations, a hydrogel that exhibits high hydration with aminimal increase in mass and height (i.e., swelling/expansion) may beuseful. Expansion due to swelling of the hydrogel generally produceseffects that may require balancing. For example, swelling enhanceselectrical conductivity, makes the hydrogel more hydrophilic, and thusmore comfortable when in contact with skin, and reduces contactresistance. However, more swelling also makes the hydrogel more stickyand less robust, and therefore more prone to breakage during applicationof current, and increases the drying out rate (although the amount ofwater left over after a specific period of dry-out depends both on therate of dry out and the initial water content). Taking these effectsinto consideration, exemplary formulations (e.g., formulations SB4A andSB4B) may incorporate a diluent that is an inert solvent that forms ahydrogel having a substantial swelling ratio (or water uptake) but whichdoes not expand upon hydration since the incoming water replaces thediluent leaving with less volume change upon hydration and swelling inwater. For example, the hydrogel formulations provided in Example 6(hydrogel formulation SB4A) and Example 7 (hydrogel formulation SB4B)that include acrylic terminated siloxane monomers may be useful. TheSB4A and SB4B hydrogel formulations demonstrated a high level ofhydration with minimal expansion, as shown in the data provided inExample 14. The silicone hydrogel formulation provided in Example 15(hydrogel formulation SB5), which exhibited increased cross-linking dueto the inclusion of trimethoylol propane trimethacrylate, demonstratedzero expansion, as shown in the data provided in Example 18. Overall,the data provided in Examples 16-19 provide that the SB5 formulation(SB5) may be useful when formed as a hydrogel tip of a nasal stimulatordevice. The expansion of the SB5 formulation upon hydration was shown tobe significantly less than earlier formulations (e.g., SB1 and SB2), andextended less than 0.5 mm beyond the boundary of the tip when thehydrogel was fully hydrated. Additionally, resistance was less than600Ω, well within requirements, and it did not increase beyond 1000Ωupon drying for up to 8 hours. The results also showed that the SB5formulation was sufficiently extracted and hydrated so as to be readyfor use after 12-24 hours of extraction in saline at 55 degrees celsius.However, the hydrophobic nature of its surface caused an increase incontact resistance, especially in contact with parts of the nasal tissuethat is especially hydrated. This problem can likely be solved by ahydrophilic surface modification or addition of a hydrating medium, aspreviously described herein. A hydrogel that is capable of high levelsof water uptake (i.e., high hydration) will typically be moreelectrically conductive. Parameters such as monomer extraction rate andelectrical resistance can be measured and the resultant values used toindicate the hydration level of the hydrogels, as provided in Examples8-12, 16, and 17. The addition of a diluent, as shown in Example 9 doesnot appear to effect hydration of the hydrogel, but may affect curerate.

Manufacturing Methods

Various manufacturing methods are also described herein. These processesmay include various ways of curing the hydrogel formulations, variousways of obtaining a suitable hydrogel shape, and various ways ofassembling the hydrogel at the tip of a nasal stimulator. Themanufacturing methods may be useful in forming the hydrogel contact ofthe disposable pronged portion of the nasal stimulator provided in FIG.2, or hydrogel contacts of nasal stimulator prongs/tips havingalternative configurations, such as the nasal stimulator prongs/tipsdescribed in U.S. application Ser. No. 14/256,915 (U.S. Publication No.2014/0316485), entitled, “NASAL STIMULATION DEVICES AND METHODS,” filedApr. 18, 2014, the contents of which were previously incorporated byreference in their entirety (the conductive hydrogels in U.S.application Ser. No. 14/256,915 are referred to as hydrogel electrodes).In general, manufacturing methods that help with scalability and storageof the shaped hydrogel may be useful. Furthermore, manufacturing methodsthat increase the volume of hydrogel at the tip of the electrode of anasal stimulator may be beneficial since this would lead to less dryingout of the hydrogel. Manufacturing methods tailored so that the hydrogelforms a bulge at the distal end of the electrode of a nasal stimulatormay also be useful.

In one variation of curing the hydrogel formulation, disposable moldsare used, e.g., as shown in FIG. 4. The disposable molds form acontinuous shell of the conductive hydrogel formulation around thesleeve, while filling the space inside the slot and the sleeve just nextto the electrode. As noted in the figure, the tube may be made from lowcost biocompatible, processable material that is transparent to UVradiation, e.g., polyethylene, polyvinylidene fluoride (PVDF),polypropylene (non-UV absorbing grades), polystyrene, ABS and the like.The tube is typically open at one end and closed at the other, and mayhave an internal diameter of about 6.0 mm, a length of about 14 mm, anda wall thickness ranging from about 0.20 to about 1.0 mm. Othervariations of the tube may have an internal diameter ranging from about3.0 to about 10 mm, and a length ranging from about 5.0 mm to about 20mm.

The disposable molds may be injection molded just in time for use in thecuring process. An exemplary assembly and curing process, as shown inFIG. 5, may track to transport parts and subassemblies, and robot toposition them. In this process, the electrodes, shaped as rods, springsor foils are assembled into the sleeves that are injection moldedseparately. The preassembled electrode and sleeve assembly may beinventoried and provided to the final assembly process depicted in FIG.5, or they may be assembled on line, as shown in FIG. 5.

The conductive hydrogel formulations may be contained in sealedcontainers that are opaque and isolated from air. The formulations mayalso be de-aerated prior to being charged into the container. In somevariations, the disposable molds are injection molded on line, and arestored in work in process inventory. Long term storage of disposablemolds is preferably avoided, since long term storage would introducedust particles into the molds, and would then require the disposablemolds to be washed or cleaned prior to use. Next, the electrodesubassembly is placed inside the disposable mold and a specified volumeof hydrogel formulation is discharged into the disposable mold. Thedisposable mold is then moved to a station in which radiation sourcesare placed in order to provide uniform radiation on all sides of thedisposable mold. Temperature is controlled by flowing nitrogen throughthe station, which also maintains the curing mixture in an oxygen freeenvironment. In this instance, the range of temperature of cure is 30-45degrees Celsius and the cure times range from about 1 to about 15minutes. The subassembly is then removed from the disposable mold andthe disposable mold discarded after the cure is complete.

In some variations, de-molding can be accomplished by application of arapid cooling pulse, e.g., by a brief immersion into water at 0 degreesCelsius. The electrode subassembly comprising a hydrogel shell may thenbe immersed in deionized water for a period of 2-24 hours in order toremove unreacted monomers and the diluent. The temperature of thedeionized water may range from about 35 to about 50 degrees Celsius orfrom about 10 to about 40 degrees Celsius. The electrode subassembly,also called the disposable unit, is then removed from the water, brieflydried to remove excess water, then packaged in a sealed pouch to beready for sterilization.

Alternative manufacturing methods for forming the hydrogel into asuitable shape for use with a nasal stimulator device are also describedherein. Some variations of the method include a dip-coating and spraytechnique. For example, the tip of a prong(s) (800) of a nasalstimulator can be dipped up and down (in the direction of the arrows)into the hydrogel (802) repeatedly, as shown in FIG. 8A, or the prong(s)used to scoop the hydrogel (802) at an angle, as shown in FIG. 8B. Herethe viscosity of the hydrogel can be adjusted so that the cavity (804)within the prong (800) is filled with the hydrogel after dipping orscooping. Additionally, a primer can be included in the hydrogelformulation to help adhere the hydrogel to the prong when dipping orscooping. The thickness of the hydrogel can be controlled by suchfactors as the rate of ascent/descent of the prong during dipping orscooping, temperature, and/or viscosity of the hydrogel. The viscosityof the hydrogel may be adjusted to be high enough to allow for shapememory before final curing. After dip-coating by either dipping orscooping, curing of the hydrogel on the prong tip can be performed usingUV light (as described above) or by thermal methods. It is understoodthat multiple dip/cure cycles can be implemented. Next, one or moreportions of the hydrogel tip can be masked so that an insulation layer(806) can be applied, e.g., by spraying or adhering, on the hydrogel tip(800) to cover and insulate those portions of the tip (800) that are notintended to be conductive, as shown in FIG. 8C. The insulation layer maycomprise any suitable insulator, e.g., a non-conductive polymer. Afterapplying the insulator, e.g., by spraying or adhering, the maskedportion (808) of the tip (800) would be conductive. Alternatively, whena mask is not used, the orientation of the hydrogel tip can becontrolled so that only insulated areas are sprayed or exposed.

The hydrogel can also be shaped first and then placed at the end of aconductor, e.g., the tip of a nasal stimulator prong. Using suchmethods, the shaped hydrogel portion can be made ahead of time and thenhydrated in bulk, and/or cleared of excess diluent and/or excessunreacted monomer in bulk, stored as a hydrogel/conductor subassemblyprior to hydration, or stored during hydration (i.e., stored by leavingin a saline solution).

Shaping of the hydrogel can be accomplished in any suitable fashion. Inone variation, the hydrogel formulation is poured into a tray and thenconductors are placed in the formulation. The formulation is then curedto form a hydrogel sheet and the sheet shaped by cutting using a lasercutter, a die cutter, a blade, etc. The cut hydrogel may be referred toas a hydrogel preform. If desired, the cured hydrogel can also be shapedto include a bulge. Alternatively, the hydrogel formulation can bepoured into a tray including individual molds or cavities having adesired shape, e.g., a bulge. The hydrogel shape formed by theindividual molds or cavities may also be referred to as a hydrogelpreform. In some instances, cutting and molding may be used incombination in a manner where the hydrogel is cut into a molded preform.

More specifically, and as shown in FIGS. 9A-9I, the hydrogel mixture (1)is first poured into a tray (2). As shown in FIG. 9B, tray (2) can beconfigured to include individual molds or cavities (3) into which thehydrogel (1) is poured. Conductors (4) may then be placed inside thehydrogel (1) prior to curing. The conductors may have any suitable formand be made from any suitable conductive material. For example, and asdepicted in FIG. 9C, the conductors may be configured as a metallicstrip (5) with holes (7), a coil spring (6), or a wire that isbent/shaped, e.g., into a loop (8), etc. These conductor configurationsmay be useful for creating a mechanical lock between the hydrogel andthe conductor. In some instances the metallic strip (5) is configuredwithout holes.

Placement of the conductors into the hydrogel formulation can includethe use of locating or capturing features. The locating and capturingfeatures can also help with insertion of the conductors to a desireddepth into the hydrogel. For example, as shown in FIG. 9D, an end ofconductor (4) can be placed on the tray with the help of a locatingfeature configured as a peg (9) or a well (10). The end of conductor (4)can also be placed with the help of a capturing feature such as plate(11), which is provided above the tray (2), as depicted in FIG. 9E. Insuch instances, plate (11) may be configured to capture conductors basedon their geometry, e.g., the conductor may have a larger section (12) atone of its ends, have a bent/deformed section (13), or have a clampingor interference fit (14) with plate (11). After the conductors have beenplaced into the hydrogel, the hydrogel is cured according to any one ofthe methods described herein. When the hydrogel has been molded/curedinto a sheet, the hydrogel can thereafter be formed into a desiredshape, e.g., by a laser cutter, a die cutter, a blade, etc. Thecomponent created by shaping (element 16 in FIG. 9G), either by cuttingor molding, may be referred to as a conductor-hydrogel subassembly(element 17 in FIG. 9G).

As shown in FIG. 9G, the conductor-hydrogel subassembly (17) can besubsequently hydrated and stored in an aqueous environment until usedfor further assembly of the tip of a nasal stimulator device, or it maybe stored dry for later processing. According to one variation, as shownin FIG. 9H, assembly of the conductor-hydrogel subassembly (17) into amolded part (20) to create the desired final tip assembly can includedropping the subassembly (17) into a hollow shaft (21) of the moldedpart (20) such that the hydrogel (16) rests on a stepped section (22)inside the shaft (21). Here the conductor (4) may be bent/deformed atthe location where it exits the shaft (21), e.g., to create a mechanicallock between the subassembly (17) and the molded part (20). Referring toFIG. 9I, a cap (24) may also be included as part of the molded part (20)by, e.g., a hinge-like mechanism (23).

The hydrogel can also be incorporated into the nasal stimulator devicetip by controlled dispensing of the hydrogel formulation, e.g., bycomputer numerical control (CNC) or robotics, or by hand, directly intoa cavity of the tip assembly. Controlled dispensing can be accomplishedby tilting mechanisms to ensure vertical alignment of the window, or theuse of guides, but is not limited thereto. It is understood that othersuitable controlled dispensing processes can be employed. A controlleddispensing method may be useful in controlling the size of the bulge ofthe hydrogel tip.

In one variation, tilting during the dispensing process may be useful incontrolling the introduction of hydrogel into the device tip. Forexample, as shown in FIG. 10A, the tip portion (25) can be tilted duringdispensing of the hydrogel formulation (26) from a dispenser device(28). The amount of tilting may vary, and can range from about 5 toabout 45 degrees. The amount of tilt may be dictated by the geometry ofthe window being filled. In general, the nasal stimulator device will betilted so that walls of the window are equidistant about a verticalcenterline of the opening, thereby allowing gravity to equally dispersethe liquid hydrogel formulation. For example, if the centerline of thewindow being filled is 45 degrees from the centerline, the nasalstimulator device is tilted (rotated) 45 degrees. Tilting may generallybe accomplished using tilting mechanisms such as pins, rollers, and/orplates, etc. FIG. 10B illustrates how a displacement roller (27) can beused to tilt tip portion (25) after the hydrogel formulation has beendispensed and cured. After dispensing the hydrogel formulation into onetip of tip portion (25), the formulation is cured and the displacementroller (27) moved to tilt the tip portion (25) in the oppositedirection. The tilting mechanisms generally tilt fixtures (e.g., flatsurfaces such as plates) upon which the tip portions have been placed toexpose each cavity to the dispenser since the cavity faces inwards onnormal orientation (when the tip portion is placed on the fixture), andfor dispensing the opening in the tip portions should face the upwarddirection. In some instances, the fixture may also have alignment pinsthat complement holes provided in the base portion of the nasalstimulator.

One or several of the tip portions may be tilted during the dispensingprocess. For example, as shown in FIG. 10C, hydrogel dispenser (28)includes multiple dispenser tips (29) and multiple tip portions (25)disposed on plate (30). Slides (not shown) coupled to multiple rollers(31) are used to tilt the multiple tip portions (25). The plate (30) canalso be moved back and forth in the direction of the arrows to achieve arocking/tilting motion.

In another variation, one or more guides disposed in or on a part of thetip portion may function to control dispensing of the hydrogel byenabling tilting or flexing of the tip portion such that the cavity issubstantially perpendicular to the hydrogel dispenser. The guides may berails and/or slots/slits that interface with a corresponding structureor geometry on a fixture to reversibly attach the tip portion to thefixture and tilt or flex the tip portion so that the cavity can befilled. For example, as shown in FIGS. 11A-11C, an inner slot (32) maybe provided in the tip portion (33) (FIG. 11A), a rail or slit (34) maybe provided within a lumen (35) of the tip portion (33) or on theoutside surface (36) of the tip portion (33) (FIG. 11B), or a slot (37)may be provided in the tip (38) of the tip portion (33) similar to alock and key combination (FIG. 11C).

In yet a further variation, the hydrogel of the tip portion can beshaped using a casting process. Here the hydrogel formulation is pouredinto a mold containing a hollow cavity of the desired shape, and thenallowed to solidify. Some variations of the mold may be configured asshown in FIG. 12A. Referring to the figure, mold (39) includes a baseblock (44), rocker plates (42), screws (43), and compression springs(45). The base block (44) includes one or more casting surfaces (41)configured to form a bulge in the hydrogel tip (i.e., a bulge castingsurface). The bulge casting surface will typically have the same radiusas a distal end of the tip portion (see element 48 in FIG. 12B), andincludes a recess such as recess (40) for creating a bulge duringcasting. Rocker plates (42) compress and secure the tip portions (seeFIG. 12 C) to the base block (44) using screws (43) and compressionsprings (45). The rocker plates may be made from a material thattransmits UV light, e.g., an acrylic material. The height of the screws(43) may be adjusted to control the amount of compression imparted byplate (42). More specifically, as shown in FIGS. 12B-12D, themanufacture of a hydrogel tip by casting may include providing a prongeddisposable tip (46) with windows (47), and orienting the distal ends(48) such that the windows (47) face the casting surface (41) of thebase block (44) of mold (39) (FIG. 12B). The distal ends (48) of thepronged tip (46) are then secured to the base block (44) by tighteningof screws (43) so that rocker plates (42) are compressed against thebase block (44) (FIG. 12 C). Again, the tips (46) are loaded into themold with the windows facing the casting surface. A UV curable hydrogelformulation as described herein can then be injected through a channel(49) in the disposable tip (46) that is fluidly connected to the distalends (48) in a manner that delivers hydrogel to the windows and thecasting surface (FIG. 12C). As stated above, the casting surfaceincludes a recess for forming a bulge in the hydrogel. After thehydrogel formulation is injected into the tip portion (46), UV light canbe applied to cure the hydrogel. Either the rocker plates or base blockcan be made from a material that transmits UV light. An exemplary UVtransmissive material comprises glass. Here the UV light is capable ofbeing transmitted through the base block (44) and distal end (48). Therocker plates (42) are then released so that the distal ends (48) can beremoved from the base block (44). As shown in FIG. 12D, the resultinghydrogel formed by the casting process has a bulge (50) that protrudesfrom window (47). Although a single mold is shown in FIGS. 12A-12D, itis understood that a ganged array of molds could be configured andemployed for large scale production.

Some methods of manufacturing include decreasing the wall thickness atthe end of the tip portions so that the volume of hydrogel can beincreased in the tip portions. In one variation, this is accomplished bymolding the tip from a single component and using a micro-moldingprocess and material. Using this process, for example, the wallthickness of the tip portion can be decreased from thickness A (shownbetween the arrows on the left) to thickness B (shown between the arrowson the right) in FIG. 13 to thereby increase the volume within the tipend. Other methods may include steps that create a high volume tosurface area ratio to maintain the desired level of hydration of thehydrogel.

Tip Assembly Methods

Methods for assembling the tip portion of a nasal stimulator device arefurther described herein. These assembly methods may be mixed andmatched with the various ways of shaping the hydrogel, as describedabove. The methods may also be used to assemble the disposable tipportion shown in FIG. 2, or tip portions having other configurations.Some variations of the tip portion may require only partial assemblybefore the hydrogel is added to them. In general, the assembly methodsinclude steps that fix the hydrogel within the tip portion, eithermechanically (e.g., by hydrating after placing the hydrogel into thetip, interference fit, screw fit, etc.), or chemically (e.g., by epoxy,bioadhesives, ultrasound, etc.).

In variations where the hydrogel formulation is dispensed into thewindow of the tip portion, the tip may include an electrode (51) havinga distal end (59) that is insert molded into a cap (52) and a flexible,frangible, or spring-like proximal end (60) comprising arms (61), asshown in FIG. 14A. The electrode (51) may include a slot (53) thatfunctions to provide mechanical retention of the hydrogel within thecavity (element 54 in FIG. 14B) of a tip assembly (element 55 in FIG.14B). In its partially assembled state, as provided in FIG. 14B, thehydrogel can be injected using a dispensing system and method asdescribed above, into cavity (54) through window (56). Here formation ofthe hydrogel bulge may be controlled by the surface tension and/or theviscosity of the uncured hydrogel.

After curing of the hydrogel, the tip assembly may be attached to anasal stimulator device as depicted in FIG. 14C. Referring to FIG. 14C,the tip assembly (55) is attached to the rest of the disposable tipportion via a retainer block (57) at the distal end of a flex tube (58)(within the prong of a stimulator device) that has a tip retainer (62 b)with a ramp surface (62). The electrode (51) of the tip assembly (55) ispushed in the direction of the arrow so that it is forced to follow theramp surface (62). The flexible/frangible nature of the electrode arms(61) allow them to snap back to their original configuration when fullyinserted to substantially surround the tip retainer (62 b). Theelectrode arms (61) may be configured to permanently deform when pulledupward in the direction of the arrow and detached from the tip retainer(62 b) so that the tip assembly cannot be reused, as shown in FIG. 14 D.

In variations where the hydrogel is preformed using, e.g., any of themethods described above, the hydrogel may be preformed as a cylinder(63) having a slot (64) for accepting an electrode (65), as shown inFIG. 15A. Here the hydrogel is an unhydrated preform that is hydratedafter the tip assembly is fully assembled. It is understood that thehydrogel preform may or may not be washed of excess unreacted monomerprior to integration into the tip assembly. During the hydrationprocess, the hydrogel preform (63) will generally swell in the directionof the arrows, fill open spaces, and expand through window (66) tocreate a stimulation (contact) surface (67). Furthermore, given that theclearance between the electrode (65) and slot (64) is small, theelectrode is typically fully contacted by the hydrogel in the initialphase of hydration (e.g., upon 20% hydration). This is a beneficialsafety feature since it ensures that when a patient uses the nasalstimulator device, the full surface of the electrode is carrying theelectrical current. An angular slot (68) on the exterior of the tipassembly opposite the window (66) can be used to align and mate the tipassembly to a corresponding structure in a dispensing cassette duringthe manufacturing process, as further described below.

In other variations, a hydrogel preform may be placed into a tipassembly that includes a hinge, e.g., a living hinge. For example, asshown in FIG. 16A, the tip assembly (69) may be configured to include afirst side (70) having a cavity (77 a) for placement of the hydrogelpreform (not shown), a window (71) that allows the hydrogel preform toexpand, a channel (72) for slidable engagement of an electrode (notshown), and a hole (73). First side (70) is coupled to a second side(74) via a living hinge (75). The second side (74) includes a cavity (77b), a tapered boss (76) that is accepted by the hole (73) when thesecond side (74) is folded over to contact the first side (70) at livinghinge (75). The tapered boss (76) and hole (73) have an interference fitand may be welded together prior to hydration of the hydrogel preform.In another example, the tip assembly may include a deflectable electrode(78) capable of being deflected in the direction of the arrow to allow ahydrogel preform (79) to be installed in the tip assembly, as shown inFIG. 16B. Here the electrode includes a hole (73) for acceptance of thetapered boss (76) when the first (70) and second (74) sides are rotatedat the living hinge (75) to close the sides together. Instead of atapered boss and hole, the sides may also be secured together using atongue and groove configuration. For example, as shown in FIG. 16C, afemale tapered groove (80) can be configured to have an interference fitwith a male tapered tongue (81). Other variations of the tip assemblyare shown in FIG. 16D, and include a hydrogel retention bar (82) to helpsecure the hydrogel within the tip and/or a living hinge (84) recessedwithin a slot (83) provided in the surface of the tip to help preventabrasion of nasal tissue.

The manufacturing methods may also employ the use of a dispensingcassette to assemble the tip assemblies in bulk. Bulk packaging mayreduce the amount of packaging materials and volume, which is convenientfor the end user. An exemplary dispensing cassette is provided in FIGS.17A-17F. Referring to FIG. 17A, the dispensing cassette (90) may includea cassette housing (85) having a proximal end (86) and a distal end(87), and an alignment block (88) coupled to the proximal end (86), anda constant force spring (89). A plurality of tip assemblies (91) can bestored in the cassette housing (85) and held in place by the constantforce spring (89), which pushes the tips (91) against the alignmentblock (88). A plurality of holes (93) are provided in the constant forcespring (89), which are spaced apart a distance equal to the length ofone tip assembly (91). When the dispensing cassette (90) is at rest, apin (92) of the alignment block (88) is not engaged with a hole (93) inthe constant force spring (89). As provided in more detail in FIG. 17B,when the dispensing cassette is at rest, a spring (94) in itsunrestrained state pushes pin (92) out of hole (93) in the constantforce spring (89), and the constant force spring (89) pushes the tips(91) (see FIG. 17A) back toward surface (95) of alignment block (88).When the dispensing cassette is activated by the user for the attachmentof the tips (91) to the rest of the nasal stimulator device (not shown)as depicted in FIG. 17C, the alignment block (88) is depressed tocompress spring (94) and allow engagement of pin (92) with constantforce spring hole (93) to release the load provided by constant forcespring (89) against the tips (91) while a tip is being attached. A wick(96) can also be provided to keep a supply of moisture in the dispensingcassette so that the hydrogel in the tips (91) do not dry outprematurely. The wick (96) may be saturated with a fluid such as saline.As previously described, the tip assemblies may include a slot (97) (asshown in FIG. 17D) configured to engage a complementary structure of thecassette housing (99) so that angular alignment of the electrodes can becontrolled. For example, as depicted in FIG. 17E, the slots (97) in thetips (91) engage ribs (98) of the cassette housing (99).

Some variations of the manufacturing method combine the electrode andtip retainer shown in FIG. 14C with the dispensing cassette described inFIGS. 17A-17C, as illustrated in FIGS. 18A-18D. First, the alignmentblock (88) is depressed in the direction of the arrow (FIG. 18A) toexpose a new tip assembly (91) that can be accessed by the prongedportion (101) of the nasal stimulator device (103) (FIG. 18B). Theelectrode (105) is aligned to attach to a connector (not shown) in theprong (101). Next, the device (103) and prongs (101) are advancedthrough the access holes (107) in the alignment block (88) until a tip(not shown) is attached as described in FIG. 14C. After attachment, thedevice (103) may be withdrawn from the alignment block (88) andcompression force on the alignment block (88) may be released in thedirection of the arrow, as shown in FIG. 18D.

If tip detachment is desired, a tip removal tool may be employed, asdepicted in FIGS. 19A-19C. Referring to FIG. 19A, tip assemblies (91)can be inserted into a cavity (111) of tip removal tool (113) thatresembles a clasp. The removal tool (113) can then be pinched tocompress the tip assemblies (91) within the removal tool (113), as shownin FIG. 19B. While maintaining the compression force, the device (103)can be pulled away from the tip removal tool (113) to detach the device(103) from the tip assemblies (91), as shown in FIG. 19C.

In yet further variations, the manufacturing methods include steps thatattach a flexible base unit to a rigid tip assembly. For example, asshown in FIG. 20A, caps (115) on hydrogel preforms (117) may beprovided. Rigid, elongate electrodes (119) may extend from the caps(115) for advancement through a flexible base (121). Segments (123)including windows (125) are attached to the flexible base (121). Asshown in the figure, segments (123) have an open top (127) so that thehydrogel preforms (117) can be loaded therein. After the electrodes(119) are advanced into the flexible base (121) the caps (115) can befixed to the flexible base, e.g., by welding. In another example, asshown in FIG. 20B, the flexible base (121) is configured to includetapered ends (129) that accept complementary structures (131) near thedistal end (133) of elongate electrodes (119).

Methods of Use

Methods for stimulating nasal or sinus tissue (and the lacrimal gland)are also described herein. In one variation, the method includes placingan arm of a nasal stimulator device against a nasal or a sinus tissue,the arm having a distal end and an electrically conductive hydrogeldisposed at the distal end; and activating the nasal stimulator deviceto provide electrical stimulation to the nasal or the sinus tissue,where the electrically conductive hydrogel is used to facilitate anelectrical connection between the nasal stimulator device and the nasalor the sinus tissue. As stated above, the conductive hydrogel maycomprise a first monomer; a second monomer; and a photoinitiator, wherethe first monomer is an acrylate monomer and the electrically conductivehydrogel has one or more characteristics that adapt it for use with anasal stimulator device. The conductive hydrogel may include monomers,diluents, photoinitiators, and other components as described herein,e.g., the components provided in Table 1 and Table 3. Again, theformulations are subjected to UV radiation to form a cross-linked,conductive hydrogel. The conductive hydrogels used in these methods mayinclude those listed in Tables 2 and 5.

Generally, when one or more nasal or sinus afferents (trigeminalafferents as opposed to olfactory afferents) are stimulated, alacrimation response is activated via a naso-lacrimal reflex. Thisstimulation may be used to treat various forms of dry eye, including(but not limited to), chronic dry eye, episodic dry eye, seasonal dryeye. To provide continuous relief of dry eye symptoms, nasolacrimalstimulation from one to five times a day may be needed. In someinstances, the stimulation may be used as a prophylactic measure totreat users which may be at an increased risk of developing dry eye,such as patients who have undergone ocular surgery such as laser visioncorrection and cataract surgery. In other instances, the stimulation maybe used to treat ocular allergies. For example, an increase in tearproduction may flush out allergens and other inflammatory mediators fromthe eyes. In some instances, the stimulation may be configured to causehabitation of the neural pathways that are activated during an allergicresponse (e.g., by delivering a stimulation signal continuously over anextended period of time). This may result in reflex habitation which maysuppress the response that a user would normally have to allergens.

EXAMPLES

The following examples further illustrate the conductive hydrogelformulations as disclosed herein, and should not be construed in any wayas limiting their scope.

Example 1: Method of Making an Electrically Conductive Hydrogel for Usewith a Nasal Stimulator Device

In a round bottom flask wrapped in aluminum foil and provided with amagnetic stirrer, introduce a first monomer, a second monomer, and aphotoinitiator. Additional monomers (e.g., a third or fourth type ofmonomer, etc.) and/or a diluent may also be added. Clamp the flask ontop of a magnetic stirrer/heater that is fitted with a nitrogen purgeline. After turning on the magnetic stirrer and nitrogen purge, mix thecontents of the flask for five minutes to form a monomer mixture. Whilethe monomers are being mixed, insert sleeves of a nasal device (e.g.,sleeve (300) shown in FIGS. 3A-3C) into disposable molds (e.g., as shownin FIG. 4) having windows or louvers that open to let in UV light. Thesleeves should be oriented vertically within the molds. Next, draw themonomer mixture from the flask into a syringe and cover the syringe withfoil. Attach a needle, e.g., a 30 gauge blunt needle, to the syringe.Insert the needle into the sleeve and fill the sleeve with the monomermixture. Next, open the louvers and irradiate the molds for about threeminutes with UV light. Thereafter, turn the molds horizontally with thelouvers facing upward and irradiate the molds for about seven minuteswith UV light. Cool the molds before removing the sleeves from them.

Example 2: Preparation of a Silicone Hydrogel IncludingMethacryloxypropyl Tris (Trimethoxysiloxy) Silane and Methanol Diluent

In a round bottom flask wrapped in aluminum foil and provided with amagnetic stirrer, the following was added:

EGMDA (Ethylene glycol dimethacyrlate) (0.081 g)

NVP (N-vinyl pyrollidone) (2.179 g)

GMA (Glyceryl monomethacrylate) (1.112 g)

DMA (Dimethyl acrylamide) (3.917 g)

Methacryloxypropyl tris (trimethyoxysiloxy) silane (2.712 g)

Lucirin (TPO) (0.081 g)

Methanol (2.88 g)

The flask was clamped on top of a magnetic stirrer/heater that wasfitted with a nitrogen purge line. The contents of the flask were thenmixed for five minutes to form a monomer mixture. While the monomerswere being mixed, the nasal device sleeves and disposable molds wereprepared as described in Example 1. The monomer mixture was then drawninto a syringe, injected into the sleeves, and irradiated as describedin Example 1. The molds were cooled before removing the sleeves fromthem.

Example 3: Silicone Hydrogel SB1

Silicone hydrogel formulation SB1 was prepared and molded into sleevesas described in Example 1. The components of the SB1 hydrogel areprovided below. A diluent was not included in the SB1 hydrogelformulation.

SB1 14020 (for kinetic study (formulated on Mar. 13, 2014) molecularmole 10 gram molar ratio weight mass frac- batch to major Monomers(g/gmole) mole (g) tion (g) monomer wt % HEMA 130.14 0.0768 10.00000.0964 0.9606 0.2152 9.5299 EGDMA 198.00 0.0018 0.3500 0.0022 0.03360.0049 0.3335 NVP 111.14 0.2969 33.0000 0.3726 3.1700 0.8315 31.4487 DMA99.13 0.3571 35.4000 0.4481 3.4006 1.0000 33.7359 allyl methacrylate126.16 0.0028 0.3500 0.0035 0.0336 0.0078 0.3335 methacryloxypropyl422.82 0.0591 25.0000 0.0742 2.4015 0.1656 23.8248 trisTrimethoxysiloxysilane lucerin 348.00 0.0024 0.8320 0.0030 0.0800 0.0067 0.7937 Total0.7969 104.9320 1.0000 10.0800 100.0000

Example 4: Silicone Hydrogel SB2

Silicone hydrogel SB2 was prepared as in Example 1. The components ofthe SB2 hydrogel are provided below. A methanol diluent was included inthe SB2 hydrogel formulation.

SB2 14021 (for kinetic study (formulated on Mar. 13, 2014) molecularmole 10 gram molar ratio weight mass frac- batch to major Monomers(g/gmole) mole (g) tion (g) monomer wt % HEMA 130.14 0.0768 10.00000.0443 0.9606 0.2152 7.4582 EGDMA 198.00 0.0018 0.3500 0.0010 0.03360.0049 0.2610 NVP 111.14 0.2969 33.0000 0.1714 3.1700 0.8315 24.6120 DMA99.13 0.3571 35.4000 0.2061 3.4006 1.0000 26.4020 allyl methacrylate126.16 0.0028 0.3500 0.0016 0.0336 0.0078 0.2610 methacryloxypropyl422.82 0.0591 25.0000 0.0341 2.4015 0.1656 18.6455 trisTrimethoxysiloxysilane lucerin 348.00 0.0024 0.8320 0.0014 0.0800 0.0067 0.6211 diluentmethanol 32.04 0.9357 29.9808 0.5401 2.88 2.6203 22.3602 Total diluent +hydrogel 1.7327 134.9128 1.0000 12.88 100.0000

Example 5: Silicone Hydrogel SB3

Silicone hydrogel SB3 was prepared and molded into sleeves as inExample 1. The components of the SB3 hydrogel are provided below. TheSB3 hydrogel formulation included a methanol diluent and the HEMAmonomers were replaced with EGDMA monomers, which are more hydrophilicthan the HEMA monomers.

SB3 (Kinetic Study 3) molecular mole 10 gram molar ratio Wt weight frac-hydrogel to major Frac- Monomers (g/gmole) tion batch (g) monomer tionEGDMA 198.00 0.0025 0.081 0.0103 0.0062 NVP 111.14 0.1203 2.179 0.49630.1681 GMA 160.00 0.0426 1.112 0.1759 0.0858 DMA 99.13 0.2424 3.9171.0000 0.3022 (3-methacry- 422.82 0.0393 2.712 0.1623 0.2092loyloxypropyl) tris(trimethyl- siloxy) silane lucerin 348.00 0.00140.080 0.0058 0.0062 Diluent methanol 32.04 0.5514 2.88 2.2751 0.2222Total 1.0000 12.9600 1.0000

Example 6: Silicone Hydrogel SB4A

Silicone hydrogel SB4A was prepared and molded into sleeves as inExample 1. The components of the SB4A hydrogel are provided below. TheSB4A hydrogel formulation included a methanol diluent and two differentacrylic terminated siloxane monomers.

SB4A (Kinetic Study 3) molecular mole 10 gram molar ratio wt weightfrac- hydrogel to major frac- Monomers (g/gmole) tion batch (g) monomertion Trimethylol 338.00 0.0019 0.131 0.0103 0.0091 propanetrimethacrylate NVP 111.14 0.0908 2.074 0.4963 0.1440 GMA 160.00 0.03221.058 0.1759 0.0735 DMA 99.13 0.1830 3.727 1.0000 0.2588 (3-methacry-422.82 0.0347 3.010 0.1894 0.2091 loyloxypropyl) tris(trimethyl- siloxy)silane lucerin 348.00 0.0011 0.080 0.0061 0.0056 diluent methanol 32.040.6563 4.32 3.5863 0.3000 Total Diluent + 1.0000 14.400 1.0000 hydrogel

Example 7: Silicone Hydrogel SB4B

Silicone hydrogel SB4B was prepared and molded into sleeves as inExample 1. The components of the SB4B hydrogel are provided below. TheSB4 hydrogel formulation also included a methanol diluent and twodifferent acrylic terminated siloxane monomers.

SB4B (Kinetic Study 3) molecular mole 10 gram molar ratio wt. weightfrac- hydrogel to major frac- Monomers (g/gmole) tion batch (g) monomertion Trimethylol 338.00 0.0019 0.137 0.0103 0.0095 propanetrimethacrylate NVP 111.14 0.0939 2.167 0.4963 0.1505 GMA 160.00 0.03331.106 0.1759 0.0768 DMA 99.13 0.1893 3.894 1.0000 0.2704 (3-methacry-422.82 0.0307 2.696 0.1623 0.1872 loyloxypropyl) tris(trimethyl- siloxy)silane lucerin 348.00 0.0011 0.080 0.0059 0.0056 Diluent methanol 32.040.6497 4.32 3.4321 0.3000 Total 1.0000 14.4000 1.0000

Example 8: Measurement of Hydration of the SB1 Hydrogel as a Function ofMonomer Extraction Rate

After curing, the hydration of the SB1 hydrogel formulation was measuredas a function of the extraction rate of unreacted DMA and NVP monomers,as shown below. The formulation was immersed in saline (NaCl indeionized water, 0.9% w/w) using 3.5 mL of saline per sleeve containingapproximately 60 mg of polymer per sleeve. The temperature was heldconstant at 55° C., and the solution was shaken in the incubated shakerat 100 rpm. Extraction was carried out for 1, 2, 3, 4, 6, 8, 12 and 24hours, with the saline extractant being replaced with fresh salinesolution after each period. The extraction process removes unreactedimpurities from the polymer and also allows it to undergo hydration.Electrical resistance is believed to be dependent on the level ofhydration of the polymer.

The extracts were analyzed by GC-MS chromatography, on an Agilent 7890AGC with Agilent 5975C mass selective quadrupole detector, monitoringN-vinyl pyrrolidone (NVP), Dimethyl acrylamide (DMA). Total ionchromatograms were recorded on each elute, and peaks identified usingpure NVP, DMA and methanol as references.

After about one hour of extraction (the terms extraction and hydrationare used interchanageably in this application), the extraction rate forthe SB1 hydrogel formulation was about 170 μg/hr for DMA (shown in FIG.21A) and about 450 μg/hr for NVP (shown in FIG. 21B).

Example 9: Measurement of Hydration of the SB2 Hydrogel as a Function ofMonomer Extraction Rate

After curing, the hydration of the SB2 hydrogel formulation was measuredas a function of the extraction rate of unreacted NVP monomers, as shownin FIG. 22A and as described in Example 8, and as a function of theextraction rate of methanol, as shown in FIG. 22B. About one hour aftercuring, the extraction rate for the SB2 hydrogel formulation was about1,150 μg/hr for NVP, which was much higher than that obtained with theSB1 hydrogel formulation. As noted above, a difference between the SB1and SB2 formulations is that SB2 contained a methanol diluent. Thepresence of the diluent substantially accelerated the extraction ofunreacted monomers from SB2, as shown by the relative rates ofextraction of NVP from SB2 and SB1 (1,150 μg/hr vs. 450 μg/hr. However,the presence of the diluent also lowered the cure rate of SB2 relativeto SB1, by reducing the effective mole fractions of each of the monomers(data not shown).

Example 10: Measurement of Hydration of the SB1 and SB2 Hydrogels as aFunction of Electrical Resistance

After curing, the hydration of the SB1 and SB2 hydrogel formulationswere measured as a function of electrical resistance over a 72 hourextraction period (monomer extraction is a process that helps completehydration of the hydrogel). Electrical resistance was measured by amultimeter set to read in serial resistance mode. One multimeter leadmakes contact with the spring of the reference sleeve and the other withthe spring of the test sleeve. The resistance measurement was readwithin 30 seconds. The resistance of the circuit, i.e., resistance otherthan the test sleeve, was estimated to be 2Ω. “Sleeve resistance,” asreferred to in the Examples, means resistance values specific to thesleeve, i.e., with the 2 kΩ removed.

From the data provided in FIGS. 23A and 23B, it is shown that for bothhydrogel formulations, the electrical resistance is high (approximately145 to 175 kΩ) after the first hour of hydration/extraction, but as thehydrogel becomes more hydrated, the resistance drops (i.e., they becomemore conductive). The data is not plotted after 8 hours of hydrationgiven the very low values.

Example 11: Measurement of Hydration of the SB2 and SB3 Hydrogels as aFunction of Electrical Resistance

After curing, the hydration of the SB2 and SB3 hydrogel formulationswere measured as a function of electrical resistance over a period ofone to 8 hours and a period of four to 72 hours, as described in Example10. The data provided in FIGS. 24A and 24B show that hydration continuesover a long period (here 72 hours). These hydrogels were still usableafter 8 hours of hydration (they were still conductive). Furthermore,the gel mass of SB3 is significantly higher than that of SB2 afterhydration. It should be noted that although the gel mass of SB3 ishigher than that of SB2, gel height is lower for SB3. This is due to thepresence of the diluent.

Example 12: Measurement of Hydration of the SB4A and SB4B Hydrogels as aFunction of Electrical Resistance

After curing, the hydration of the SB4A and SB4B hydrogel formulationswere measured as a function of electrical resistance over a period of144 hours. The data provided in FIG. 25 also shows that the hydrogelsremain hydrated over a long period of time, and become more conductiveas hydration increases.

Example 13: SB2 and SB3 Hydrogel Expansion Due to Hydration

Mass and height for the SB2 and SB3 hydrogel casts were measured todetermine swelling of the hydrogels as a function of hydration. Themeasurements are provided in FIGS. 26A and 26B. Replacement of HEMAmonomers with EGDMA monomers in SB3 rendered it more hydrophilic, whichresulted in an increase in water uptake relative to SB2, and thus, alarger mass.

Example 14: SB4A and SB4B Hydrogel Expansion Due to Hydration

Mass and height for the SB4A and SB4B hydrogels were measured andcompared to that of the SB3 hydrogel to determine swelling of thehydrogels as a function of hydration, as shown in FIGS. 27A and 27B. TheSB4A and SB4B hydrogels, which exhibited high hydration (see Example 12)expanded less than the more hydrophilic SB3 hydrogel. Thus, with theSB4A and SB4B hydrogels, higher conductance was achieved with lessswelling/expansion.

Example 15: Silicone Hydrogel SB5

Silicone hydrogel formulation SB5 was prepared and molded into sleevesas described in Example 1. The components of the SB5 hydrogel areprovided below. A methanol diluent was included in the SB5 hydrogelformulation.

SB5 molecular mole 10 gram molar ratio wt. weight frac- hydrogel tomajor frac- Monomers (g/gmole) tion batch (g) monomer tion Trimethylol338.00 0.0021 0.119 0.0151 0.01186 propane trimethacrylate NVP 111.140.0686 1.278 0.4957 0.12779 GMA 160.00 0.0243 0.653 0.1760 0.06530 DMA99.13 0.1383 2.299 1.0000 0.22992 (3-methacry- 422.82 0.0224 1.5910.1623 0.15914 loyloxypropyl) tris(trimethyl- siloxy) silane lucerin348.00 0.0011 0.067 0.0082 0.00666 Diluent methanol 32.04 0.7431 3.9935.3738 0.39934 Total 1.0000 10.0000 1.0000

In the SB5 formulation, the UV initiator, diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (CAS #75980 60-8, Lucirin TPO),was selected since it is capable of being activated by UV radiation inthe wavelength range of 400-450 nm, a band that is transmitted by thesleeve material (Versaflex OM3060-1, a styrene-ethylene/butylene-styrenecopolymer). Addition of trimethylol propane trimethacrylate enhancedcross-link density and rendered the mixture more resistant to dry out.

Example 16: Measurement of Hydration of the SB5 Hydrogel as a Functionof Monomer Extraction

After curing, the hydration of the SB5 hydrogel was measured as afunction of the extraction rate of unreacted DMA and NVP monomers, andmethanol, as shown in FIGS. 28A-28C, and as similarly described inExample 8. Briefly, the extracts were analyzed by GC-MS chromatography,on an Agilent 7890A GC with Agilent 5975C mass selective quadrupoledetector, monitoring N-vinyl pyrrolidone (NVP), Dimethyl acrylamide(DMA), and methanol (MeOH). Total ion chromatograms were recorded oneach elute, and peaks identified using pure NVP, DMA, and methanol asreferences. The data in the graphs provided in FIGS. 28A-28C show thatthe rate of extraction of methanol is fastest followed by that of DMA.Extraction of NVP is the slowest. The extraction rate depends solely onthe solubility of each species in saline at the temperature of hydration(55 degrees celsius), since the swelling of the hydrogel network is thesame in all cases. As provided in the graphs, the extraction rates ofall species appear to reach a low plateau after 24 hours of hydration.Based on these results, it was concluded that the SB5 hydrogel was readyto use after 24 hours of hydration.

Example 17: Measurement of Hydration of the SB5 Hydrogel as a Functionof Electrical Resistance

After curing, the hydration of the SB5 hydrogel formulation was measuredas a function of electrical resistance over different periods ofextraction, similar to that described in Examples 10-12. As shown inFIG. 29, the electrical resistance dropped significantly upon hydrationcaused by extraction with saline. The electrical resistance of the SB5hydrogel reached a level of greater than 0.6 kΩ after 12 hours ofextraction, and a lower plateau after approximately 24 hours ofextraction.

Example 18: SB5 Hydrogel Expansion Due to Hydration

Mass and height (expansion) for the SB5 hydrogel casts were measured todetermine swelling of the hydrogels as a function of hydration (andextraction period). Referring to the data table in FIG. 30A, at 48hours, the hydration percentage (defined as100*(M_(48 hours)−M_(0 hours))/M48 hours, where M is mass in grams) ofSB5 (42-05) is calculated to be about 35.5%, which was significantlyless than that of SB1 (42-01) and SB2 (42-02). The reduced hydrationpercentage may be attributed to the increased crosslink density andincreased hydrophobicity of SB5 relative to SB1 and SB2. Thus, benefitsof the SB5 hydrogel may be that it is capable of achieving a level ofelectrical conductivity sufficient to perform its electrical functionwhile also having a relatively low level of hydration, and that itsprocessability is improved. The increased cross-link density alsoappeared to raise the glass transition temperature of the unhydratedhydrogel network (data not shown). These changes in the composition ofthe SB5 hydrogel relative to the SB1 and SB2 hydrogels may improve itsdrying out time and its robustness to shear forces induced by rubbingagainst nasal tissue.

Referring to the Gel Mass vs. Hydration Duration graph provided in FIG.30B, the SB5 hydrogel reached a threshold of hydration at about 24 hoursof extraction, in contrast to the SB1 and SB2 hydrogels in whichhydration continued to increase gel mass until about 72 hours (see,e.g., SB2 data in Example 13). This is consistent with the lowerhydration percentage of SB5.

Provided in FIG. 30C is a Gel Expansion vs. Hydration Duration graph,which shows the data obtained from recording the increase in height ofthe SB5 hydrogel obtained from optical photos of hydrated sleeves. Thedata indicated that gel height reached a plateau after about 24 hours ofextraction, in contrast to the SB1 and SB2 hydrogels, which continued toshow increases in gel height up to and beyond 72 hours of extraction bysaline under identical conditions (see, e.g., SB2 data in Example 13).

Overall, the data for the SB5 hydrogel showed that its equilibrium watercontent was about 35%. Referring to Example 15, the amount of methanol(diluent) used in this formulation is about 39.9%. These values indicatethat the SB5 hydrogel is a zero expansion hydrogel. The data provided ongel height expansion showed an increase from 5.0 mm (measured prior tohydration) to 5.2 mm (after completion of hydration at about 24 hours),which indicates that an increase in about 4% is attributable toadditional complexation of water molecules by the polymeric networkrelative to methanol.

Example 19: Contact Angle of the Silicone SB5 Hydrogel Formulation

The contact angle of the SB5 hydrogel used as an electrical contact atthe tip of a nasal stimulator device was measured by placing 1 μl ofdeionized water on its surface, then photographing the drop using aLeica M-80 microscope having a L80 nmnm digital camera, and having theLAS version 4.3.0 optical capture software. The contact angle wasestimated from the photograph. The measurement was repeated using anelectrical contact tip that had been hydrated by immersion intodeionized water for 30 minutes just prior to measurement. The contactangle was measured to be 90 degrees in both cases. These resultsindicate that the surface of SB5 is hydrophobic, even though the overallgel mass is highly hydrophilic. Thus, the SB5 hydrogel appears to have acomplex polymer morphology comprised of a hydrophilic core and ahydrophobic surface, e.g., as shown in FIG. 7.

Example 20: Biocompatibility of the SB5 Hydrogel Formulation

MEM studies were performed on SB5 hydrogel samples hydrated in salinefor 12 and 24 hours at 55 degrees celsius to determine thebiocompatibility of the hydrogel, as shown below. The studies werecompleted by Acta Laboratories, Inc., in accordance with USP 36/NF 31Supplement 2, (87) Biological Activity Tests, InVitro, Elution Test.

KS5 14043 12 hrs Elution Results % Intracytoplasmic Confluent % Roundand % Cell Culture Granules Monolayer Loosely Attached Lysis GradeReactivity Sample # 1 100 (+) 0 0 0 None Sample # 2 100 (+) 0 0 0 NoneReagent Control # 1 100 (+) 0 0 0 None Reagent Control # 2 100 (+) 0 0 0None Negative Control # 1 100 (+) 0 0 0 None Negative Control # 2 100(+) 0 0 0 None Positive Control # 1 0 (−) 0 100 4 Severe PositiveControl # 2 0 (−) 0 100 4 Severe

KS5 14043 12 hrs Elution Results % Intracytoplasmic Confluent % Roundand % Cell Culture Granules Monolayer Loosely Attached Lysis GradeReactivity Sample # 1 100 (+) 0 0 0 None Sample # 2 100 (+) 0 0 0 NoneReagent Control # 1 100 (+) 0 0 0 None Reagent Control # 2 100 (+) 0 0 0None Negative Control # 1 100 (+) 0 0 0 None Negative Control # 2 100(+) 0 0 0 None Positive Control # 1 0 (−) 0 100 4 Severe PositiveControl # 2 0 (−) 0 100 4 Severe

The invention claimed is:
 1. A hydrogel electrode for electricalstimulation of nasal tissue, wherein the hydrogel electrode is made froma formulation comprising a mixture of: glycerol monomethacrylate;trimethylol propane trimethacrylate; dimethylacrylamide;N-vinylpyrrolidone; 2,4,6-trimethylbenzoyl-diphenylphosphine oxide; andmethanol.